VEGFA amplification/increased gene copy number and VEGFA mRNA expression in renal cell carcinoma with TFEB gene alterations
VEGFA amplification/increased gene copy number and VEGFA mRNA expression in renal cell carcinoma with TFEB gene alterations
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DOI：
10.1038/s41379-018-0128-1
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发表时间：
2019-02-01
期刊：
影响因子：
7.5
通讯作者：
Martignoni, Guido
中科院分区：
文献类型：
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作者：
Calio, Anna;Brunelli, Matteo;Martignoni, Guido
血管内皮生长因子A （VEGFA）的扩增最近被报道在TFEB扩增的肾细胞癌中，无论TFEB扩增水平如何。我们试图通过荧光原位杂交（FISH）和原位杂交（RNAscope 2.5）在一系列10例TFEB基因发生扩增和/或重排改变的肾细胞癌中测定VEGFA扩增和VEGFA mRNA表达（t（6;11）肾细胞癌）。8例显示TFEB基因重排，其余2例显示高水平的TFEB基因扩增（bbb10个荧光信号拷贝），但无重排证据。在8例t（6;11）例肾细胞癌（TFEB重排病例）中，1例TFEB基因高水平扩增，2例TFEB基因拷贝数增加（荧光信号3-4拷贝）。这三个案例表现得咄咄逼人。通过FISH检测，3例TFEB扩增的肾细胞癌均扩增出VEGFA， 2例侵袭性肾细胞癌中VEGFA基因拷贝数增加，TFEB荧光信号重叠增加。总体而言，10例患者中有8例（80%）出现VEGFA mRNA表达；其中，3例TFEB高水平扩增，1例TFEB重排伴拷贝数增加，4例TFEB重排伴拷贝数不增加。总之，VEGFA扩增/基因拷贝数增加和VEGFA mRNA表达增加发生在TFEB扩增的肾细胞癌中，但也发生在具有侵袭性行为的t（6;11）肾细胞癌亚群中，以及未扩增的常规t（6;11）肾细胞癌中，这表明即使没有TFEB扩增，VEGFA也是这些肿瘤的潜在治疗靶点。我们最后建议，所有表现出形态学特征提示t（6;11）肾细胞癌和所有未分类肾细胞癌的肾肿瘤，无论是高级别还是低级别，都应进行免疫组织化学检测组织蛋白酶K和/或Melan-A，如果其中一个呈阳性，则检测TFEB基因改变和VEGFA基因扩增。
Amplification of vascular endothelial growth factor A (VEGFA) has been recently reported in TFEB-amplified renal cell carcinomas regardless the level of TFEB amplification. We sought to determine VEGFA amplification by fluorescent in situ hybridization (FISH) and VEGFA mRNA expression by in situ hybridization (RNAscope 2.5) in a series of 10 renal cell carcinomas with TFEB gene alterations, either amplification and/or rearrangement (t(6;11) renal cell carcinoma). TFEB gene rearrangement was demonstrated in eight cases, whereas the remaining two cases showed a high level of TFEB (>10 copies of fluorescent signals) gene amplification without evidence of rearrangement. Among the eight t(6;11) renal cell carcinomas (TFEB-rearranged cases), one case displayed a high level of TFEB gene amplification and two showed increased TFEB gene copy number (3-4 copies of fluorescent signals). Those three cases behaved aggressively. By FISH, VEGFA was amplified in all three cases with TFEB amplification and increased VEGFA gene copy number was observed in the two aggressive cases t(6;11) renal cell carcinomas with an overlapping increased number of TFEB fluorescent signals. Overall, VEGFA mRNA expression was observed in 8 of 10 cases (80%); of these 8 cases, 3 cases showed high-level TFEB amplification, one case showed TFEB rearrangement with increased TFEB gene copy number, whereas four showed TFEB gene rearrangement without increased copy number. In summary, VEGFA amplification/increased gene copy number and VEGFA mRNA expression occur in TFEB-amplified renal cell carcinoma, but also in a subset of t(6;11) renal cell carcinoma demonstrating aggressive behavior, and in unamplified conventional t(6;11) renal cell carcinoma suggesting VEGFA as potential therapeutic target in these neoplasms even in the absence of TFEB amplification. We finally propose that all the renal tumors showing morphological characteristics suggesting t(6;11) renal cell carcinoma and all unclassified renal cell carcinomas, either high grade or low grade, should immunohistochemically be evaluated for cathepsin K and/or Melan-A and if one of them is positive, tested for TFEB gene alteration and VEGFA gene amplification.